SUMO Signaling by Hypoxic Inactivation of SUMO-Specific Isopeptidases

Abstract

Post-translational modification of proteins with ubiquitin-like SUMO modifiers is a tightly regulated and highly dynamic process. The SENP family of SUMO-specific isopeptidases comprises six cysteine proteases. They are instrumental in counterbalancing SUMO conjugation, but their regulation is not well understood. We demonstrate that in hypoxic cell extracts, the catalytic activity of SENP family members, in particular SENP1 and SENP3, is inhibited in a rapid and fully reversible process. Comparative mass spectrometry from normoxic and hypoxic cells defines a subset of hypoxia-induced SUMO1 targets, including SUMO ligases RanBP2 and PIAS2, glucose transporter 1, and transcriptional regulators. Among the most strongly induced targets, we identified the transcriptional co-repressor BHLHE40, which controls hypoxic gene expression programs. We provide evidence that SUMOylation of BHLHE40 is reversed by SENP1 and contributes to transcriptional repression of the metabolic master regulator gene PGC-1α. We propose a pathway that connects oxygen-controlled SENP activity to hypoxic reprogramming of metabolism.

SUMO-specific proteases and isopeptidases of the SENP family at a glance

“…Several lines of evidence indicate that this is at least partially due to changes in the activity or abundance of SENPs. Reduced activity of SENPs has been described under thermal, oxidative or hypoxic stress (Kunz et al, 2016;Pinto et al, 2012;Xu et al, 2008). An emerging aspect of SENP regulation is their redox-dependent regulation, suggesting SENPs function as cellular redox sensors.…”

Hypoxia-induced Changes in SUMO Conjugation Affect Transcriptional Regulation Under Low Oxygen

“…Proteins that were only found more abundant in the unlabeled (Light) form in both experiments (upper left square), were rejected as external contaminants (in a red circle). (16,41). On the other hand, our analysis also identified proteins with altered sumoylation levels (Table I and Table III, see also supplementary Files S4), whose expression levels did not seem to significantly differ between normoxia and hypoxia.…”

“…For example, SENP1, which can be induced in hypoxia (14), was found to contribute to HIF-1␣ stability during hypoxia (15). On the other hand, enhanced SUMOylation of a subset of cellular proteins observed 24 h into hypoxic exposure (16), was linked to inactivation of SENP1 and SENP3. Interestingly, in addition to regulatory sumoylation of individual target proteins, hypoxia or ischemia also cause global changes in the SUMO proteome or "SUMOome" (17)(18)(19).…”

SUMO system – a key regulator in sarcomere organization

“…Mild levels of reactive oxygen species (ROS) were shown to stimulate disulfide bond formation between catalytic cysteine residues of the E1 and E2 enzymes, and as a result, global SUMOylation level was reduced [71]. SENPs, particularly SENP1 and SENP3, were reported to act as a redox sensor under hypoxic stress [72]. Hypoxic stress led to strong SUMO1 and SUMO2/3 conjugate formation and was accompanied by reduced catalytic activity of SENPs.…”

“…Hypoxic stress led to strong SUMO1 and SUMO2/3 conjugate formation and was accompanied by reduced catalytic activity of SENPs. The redox sensing function of SENPs is important for cellular metabolic reprogramming in order to adapt cells in low‐oxygen environment [72]. Upon heat shock, a strong enrichment in global poly‐SUMOylation of proteins was observed [73].…”